PROJECT SUMMARY/ABSTRACT Exposure to chiral polychlorinated biphenyls (PCBs) has been implicated as risk factor for developing neurodevelopmental disorders; however, there is a fundamental gap in our understanding of metabolic factors that modulate levels of neurotoxic PCB enantiomers in the developing brain. Because in vitro studies suggest that PCBs may cause neurodevelopmental disorders in an enantioselective manner, this gap prevents epidemiological studies from fully characterizing associations between neurodevelopmental disorders and environmental PCB exposures. Therefore, there is a critical need to understand how differences in metabolic factors, in particular cytochrome P450 (P450) isoform levels and polymorphisms, affect chiral signatures (i.e., levels of neurotoxic enantiomers of PCBs) in target tissues and contribute to an inter-individual variability in chiral signatures. The long- term goal is to determine how inter-individual differences in enantioselective PCB metabolism affect the susceptibility to PCB-mediated neurodevelopmental disorders following environmental exposures and, ultimately, reduce the burden of these diseases. The objective of this R21 project is to test the central hypothesis that inter-individual differences in the composition of the P450 enzyme system, including both P450 isoform levels and polymorphisms, result in different chiral signatures of retained PCBs, and that chiral signatures are similar across tissues within an individual. The rationale for the proposed studies is that, once the link between the P450 enzyme system and PCB chiral signature has been established, the relationship between exposure and metabolism can be studied in a human population at risk of developing a neurodevelopmental disorder. Guided by strong preliminary data, the central hypothesis will be tested by pursuing two Specific Aims: 1) Determine the relationship between the composition of hepatic P450 enzymes in individual human liver microsomes and the enantioselective metabolism of PCBs in vitro; and 2) assess the relationship between levels of PCB enantiomers in human postmortem liver and brain samples and P450 expression in these tissues. In Aim 1, we will study the metabolism of PCB enantiomers with individual human liver microsomes and relate metabolism rates to levels of P450 enzymes and polymorphisms. In Aim 2, we will measure levels of PCB enantiomers in postmortem tissues to demonstrate that chiral PCB signatures are related to the composition of P450 enzymes and comparable in different tissues from the same donor. These studies will characterize the link between variations in the P450 enzyme system in target tissues and differences in the chiral PCB signatures among humans. The proposed research is innovative because it uses state-of-the-art methods to characterize the enantiomer composition of PCBs in human tissues, such as the brain, and advances our understanding of the underlying metabolic processes. This contribution is significant because understanding the link between P450 enzymes and levels of neurotoxic enantiomers of PCBs will allow us to further study individual risks of developing a neurodevelopmental disorder and develop interventions to reduce their impact on individuals, families and society.